Process for preparing acid salts of γ-(piperidyl)butyric acid

ABSTRACT

At least one of a Rh catalyst, a Pd catalyst or a Ru catalyst is used as a catalyst in preparing the salt of γ-(piperidyl)-butyric acid (2) by hydrogenating the salt of γ-(pyridyl)butyric acid (1) [preferably the salt of γ-(pyridyl)butyric acid (1) obtained in the undermentioned steps (a) and (b) and containing not more than 3% by weight of salt of bis(pyridylethyl)acetic acid (3)] in a solvent in the presence of a catalyst: 
     (a) reacting the vinylpyridine (4) with the diester of malonic acid (5) in the presence of a base to give the 2-(pyridylethyl)malonic acid diester (6), and 
     (b) hydrolyzing and decarboxylating the 2-(pyridylethyl)malonic acid diester (6) obtained in the step (a) in an acidic aqueous solution to give the salt of γ-(pyridyl)butyric acid (1).

FIELD OF THE INVENTION

The present invention relates to a novel process for preparing a salt ofγ-(piperidyl)butyric acid with an acid, the salt being represented bythe formula (2)

wherein R is a hydrogen atom or an alkyl group, and A is an acid[hereinafter referred to as “salt of γ-(piperidyl)butyric acid (2)”].

The salt of γ-(piperidyl)butyric acid (2) is a compound which is usefulas an intermediate for a pharmaceutical chemical by itself or in theform of a γ-(piperidyl)butyric acid liberated from the acid.

BACKGROUND OF THE INVENTION

The salt of γ-(piperidyl)butyric acid (2) can be prepared byhydrogenating a salt of γ-(2-pyridyl)butyric acid with an acid forconversion of the pyridine ring to a piperidine ring. It is known toprepare the salt of γ-(piperidyl)butyric acid (2) by hydrogenating asalt of (γ-pyridyl)butyric acid with an acid using a platinum oxide as acatalyst [J. Am. Chem. Soc., 69,2461 (1947)].

However, the above-mentioned conventional process hydrogenates the saltof γ-(2-pyridyl)butyric acid with an acid at a concentration of 2% inthe reaction mixture, namely a much diluted salt, consequently leadingto a low reactor efficiency and a low productivity. Thus the process isnot practical.

The above-mentioned process poses a further problem of necessitating alarge amount of platinum oxide as the catalyst. The foregoingpublication teaches the use of platinum oxide in an amount of as largeas 4.3% by weight in terms of Pt based on a γ-(2-pyridyl)butyric acidhydrochloride.

No investigation has been heretofore made about the use of othercatalysts than platinum oxide for the hydrogenation of a salt ofγ-(pyridyl)butyric acid with an acid. It is an object of the presentinvention to provide a catalyst capable of hydrogenating a salt ofγ-(pyridyl)butyric acid with an acid to efficiently convert the pyridinering to a piperidine ring, providing a process for preparing a salt ofγ-(piperidyl)butyric acid (2) with a high productivity.

DISCLOSURE OF THE INVENTION

The present inventors conducted extensive research to overcome theforegoing prior art problems and made the following findings about thecatalyst and raw materials useful in preparing a salt ofγ-(piperidyl)butyric acid (2). The present invention was completed basedon the novel findings.

<Catalyst>

When a Rh catalyst, a Pd catalyst or a Ru catalyst is used as thecatalyst in hydrogenating a salt of γ-(pyridyl)butyric acid with anacid, the salt thereof being represented by the formula (1)

wherein R is a hydrogen atom or an alkyl group, and A is an acid[hereinafter referred to as “salt of γ-(pyridyl)butyric acid (1)”], thesalt of γ-(piperidyl)butyric acid (2) can be prepared in a relativelyshort time with a high productivity. When these catalysts are used,unexpectedly the hydrogenation of salt of γ-(pyridyl)butyric acid (1) iscompleted in a short time even at a very low hydrogen pressure ascompared with the hydrogenation of a free γ-(pyridyl)butyric acid.

<Raw Materials>

The salt of γ-(pyridyl)butyric acid (1) can be prepared by carrying outthe steps of:

(a) reacting a vinylpyridine compound represented by the formula (4)

wherein R is as defined above [hereinafter referred to as “vinylpyridine(4)”] with a diester of malonic acid represented by the formula (5)

wherein R¹ and R² are the same or different and each represents an alkylgroup [hereinafter referred to as “diester of malonic acid (5)”] in thepresence of a base to give a diester of 2-(pyridylethyl)malonic acidrepresented by the formula (6)

wherein R, R¹ and R² are as defined above [hereinafter referred to as“2-(pyridylethyl)malonic acid diester (6)”], and

(b) hydrolyzing and decarboxylating the 2-(pyridylethyl)malonic aciddiester (6) prepared in the step (a) in an acidic aqueous solution.

When the salt of γ-(piperidyl)butyric acid (2) is prepared byhydrogenation of the salt of γ-(pyridyl)butyric acid (1) obtained in thesteps (a) and (b), the specific impurities present in the salt ofγ-(pyridyl)butyric acid (1) adversely affect the reaction time forhydrogenation and the purity of the obtained salt ofγ-(piperidyl)butyric acid (2).

Stated more specifically, the process of preparing the salt ofγ-(pyridyl)butyric acid (1) produces, as a by-product, a salt ofbis(pyridylethyl)acetic acid with an acid, the salt thereof beingrepresented by the formula (3)

wherein R and A are as defined above [hereinafter referred to as “saltof bis(pyridylethyl)acetic acid (3)”].

When the salt of γ-(pyridyl)butyric acid (1) containing the salt ofbis(pyridylethyl)acetic acid (3) is hydrogenated, the reaction tends toinvolve a longer time and a high-purity salt of γ-(piperidyl)butyricacid (2) is difficult to produce.

If not more than 3% by weight of the salt of bis(pyridylethyl)aceticacid (3) is present in the salt of γ-(pyridyl)butyric acid (1), thehydrogenation is completed in a very short time and a high-purity saltof γ-(piperidyl)butyric acid (2) can be easily produced.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a process forpreparing the salt of γ-(piperidyl)butyric acid (2), the processcomprising the step of hydrogenating the salt of γ-(pyridyl)butyric acid(1) [preferably the salt of γ-(pyridyl)butyric acid (1) obtained bycarrying out the undermentioned steps (a) and (b) and containing notmore than 3% by weight of salt of bis(pyridylethyl)acetic acid (3)] in asolvent in the presence of a catalyst, the process being characterizedin that the catalyst is a Rh catalyst, a Pd catalysts or a Ru catalyst:

(a) reacting the vinylpyridine (4) with the diester of malonic acid (5)in the presence of a base to give the 2-(pyridylethyl)malonic aciddiester (6), and

(b) hydrolyzing and decarboxylating the 2-(pyridylethyl)malonic aciddiester (6) obtained in the step (a) in an acidic aqueous solution togive the salt of γ-(pyridyl)butyric acid (1).

According to the present invention, the salt of γ-(piperidyl)butyricacid (2) can be prepared in a relatively short time with a highproductivity. Especially if the salt of γ-(pyridyl)butyric acid (1) tobe hydrogenated is one prepared in the steps (a) and (b) and containingnot more than 3% by weight of salt of bis(pyridylethyl)acetic acid (3),the hydrogenation is completed in a shorter time and a high-purity saltof γ-(piperidyl)butyric acid (2) can be easily prepared.

BEST MODE FOR CARRYING OUT THE INVENTION

Salt of γ-(pyridyl)butyric acid (1)

The salt of γ-(piperidyl)butyric acid (2) can be prepared byhydrogenation of the salt of γ-(pyridyl)butyric acid (1). R in theformula (1) representing the salt of γ-(pyridyl)butyric acid (1) is ahydrogen atom or an alkyl group. Preferred alkyl group is a lower alkylgroup having 1 to 4 carbon atoms. A in the formula (1) is an acid.Examples of the acid are mineral acids such as hydrochloric acid andsulfuric acid, and organic acids such as p-toluenesulfonic acid andtrifluoromethanesulfonic acid.

Specific examples of the salt of γ-(pyridyl)butyric acid (1) are saltsof γ-(pyridyl)butyric acids with other acids. Useful γ-(pyridyl)butyricacids include, for example, γ-(2-pyridyl)butyric acid,γ-(3-pyridyl)butyric acid, γ-(4-pyridyl)butyric acid,γ-(5-methyl-2-pyridyl)butyric acid, γ-(6-methyl-2-pyridyl)butyric acid,γ-(4-methyl-3-pyridyl)butyric acid, γ-(2-methyl-5-pyridyl)butyric acid,γ-(5-ethyl-2-pyridyl)butyric acid, etc. Examples of other acids includehydrochloric acid, sulfuric acid and like mineral acids,p-toluenesulfonic acid, trifluoro-methanesulfonic acid and like organicacids.

Preparation of salt of γ-(pyridyl)butyric acid (1)

The salt of γ-(pyridyl)butyric acid (1) can be prepared by conventionalprocesses. For example, it can be prepared by hydrolysis anddecarboxylation of 2-(pyridylethyl)malonic acid diester (6) in an acidicaqueous solution (step (b)). The 2-(pyridylethyl)malonic acid diester(6) can be produced as by reacting the vinylpyridine (4) with thediester of malonic acid (5) in the presence of a base (step (a)).

<Step (a)>

The reaction in the step (a) is so-called “Michael addition reaction”.Examples of the vinylpyridine (4) are 2-vinylpyridine, 3-vinylpyridine,4-vinylpyridine, 5-methyl-2-vinylpyridine, 6-methyl-2-vinylpyridine,4-methyl-3-vinylpyridine, 2-methyl-5-vinylpyridine,5-ethyl-2-vinylpyridine and the like.

R¹ and R² in the formula (5) representing the diester of malonic acid(5) are the same or different and each represents an alkyl group.Preferred alkyl group is a lower alkyl group having 1 to 4 carbon atoms.Examples of the diester of malonic acid (5) are dimethyl malonate,diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutylmalonate and diisobutyl malonate.

The 2-(pyridylethyl)malonic acid diester (6) can be efficiently formedwhen the diester of malonic acid (5) is used in an amount of at least 1mole, preferably 1 to 3 moles, more preferably 1.5 to 2.5 moles, permole of the vinylpyridine (4). If the amount of diester of malonic acid(5) used is less than 1 mole per mole of the vinylpyridine (4), thereaction is likely to produce by-products.

Useful bases include those conventionally used in the Michael additionreaction. Preferred base is alkali metal alkoxide. Examples of thealkali metal alkoxide are methoxide, ethoxide, propoxide, isopropoxide,2-methyl-1-propoxide or 2-methyl-2-propoxide of lithium, sodium,potassium or cesium.

The reaction efficiently proceeds when the base is used in an amount of0.05 to 1 mole, preferably 0.1 to 0.5 mole, per mole of thevinylpyridine (4). The amount of the base less than the above range isresponsible for an extended reaction time, whereas the amount thereofexceeding the above range is liable to result in the formation ofby-products.

The Michael addition reaction in the step (a) can be carried out in asolvent. Useful solvents are, for example, alcohols and the like.Examples of the alcohol are alcohols having 1 to 4 carbon atoms such asmethyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol,2-methyl-1-propyl alcohol and the like. The amount of the solvent usedis 0.1 to 2 parts by weight, preferably 0.3 to 1 part by weight, perpart by weight of the vinylpyridine (4).

The Michael addition reaction in the step (a) can be conducted, forexample, by adding dropwise the vinylpyridine (4) over a period of 0.5to 2 hours to a mixture of a base, the diester of malonic acid (5) andoptionally a solvent with stirring at 75 to 110° C. After dropwiseaddition of vinylpyridine (4), the mixture may be maintained at the sametemperature for 2 to 8 hours to complete the reaction, giving2-(pyridylethyl)malonic acid diester (6) in a high yield.

<Step (b)>

The salt of γ-(pyridyl)butyric acid (1) can be prepared by hydrolyzingand decarboxylating the 2-(pyridylethyl)malonic acid diester (6) in anacidic aqueous solution at the step (b).

For example, the salt of γ-(pyridyl)butyric acid (1) can be prepared byhydrolyzing and decarboxylating the reaction mixture obtained in thestep (a) and containing the 2-(pyridylethyl)malonic acid diester (6), orby hydrolyzing and decarboxylating the purified 2-(pyridylethyl)malonicacid diester (6) isolated from the reaction mixture obtained at the step(a).

Examples of the acidic aqueous solution are aqueous solutions of acidssuch as hydrochloric acid, sulfuric acid and like mineral acids,p-toluenesulfonic acid, trifluoromethanesulfonic acid and like organicacids.

The hydrolysis and decarboxylation can be efficiently carried out whenthe acid (acidic aqueous solution) is used in an amount sufficient toacidify the mixed solution comprising the 2-(pyridylethyl)malonic aciddiester (6) and the acidic aqueous solution.

For example, when hydrolyzing and decarboxylating the purified2-(pyridylethyl)malonic acid diester (6) isolated from the reactionmixture after Michael addition reaction in the step (a), at least oneequivalent, preferably 1.1 to 2 equivalents, of the acid is usedrelative to the 2-(pyridylethyl)malonic acid diester (6).

In hydrolyzing and decarboxylating the reaction mixture resulting fromthe Michael addition reaction in the step (a), one equivalent,preferably 1.1 to 2 equivalents, of the acid is used relative to thetotal amount of 2-(pyridylethyl)malonic acid diester (6) and the baseused in the Michael addition reaction, both contained in the reactionmixture.

The hydrolysis and decarboxylation in the step (b) can be performed, forexample, by mixing the 2-(pyridylethyl)malonic acid diester (6) and theacidic aqueous solution and maintaining the mixture with stirring at 60to 120° C., preferably 90 to 110° C. for 8 to 12 hours. After completionof the reaction, the reaction mixture is concentrated, the precipitateis separated by filtration and the filtrate is cooled, giving crystalsof salt of γ-(pyridyl)butyric acid (1).

<Purification of salt of γ-(pyridyl)butyric acid (1)>

In the Michael addition reaction at the step (a), a side reaction occursto react 2 molecules of vinylpyridine (4) with one molecule of diesterof malonic acid (5), producing a diester of 2,2-bis(pyridylethyl)malonicacid represented by the formula (7)

wherein R, R¹ and R² are as defined above (hereinafter referred to as“2,2-bis(pyridylethyl)malonic acid diester (7)”). The2,2-bis(pyridylethyl)malonic acid diester (7) is hydrolyzed anddecarboxylated in the step (b), whereby the salt ofbis(pyridylethyl)acetic acid (3) is produced.

The 2-(pyridylethyl)malonic acid diester (6) isolated by distillationfrom the reaction mixture after the Michael addition reaction in thestep (a) is hydrolyzed and decarboxylated, thereby producing the salt ofγ-(pyridyl)butyric acid (1) free of the salt of bis(pyridylethyl)aceticacid (3).

When the crystals of salt of γ-(pyridyl)butyric acid (1) obtained in thestep (b) contain the salt of bis(pyridylethyl)acetic acid (3), desirablythe concentration of the salt of bis(pyridylethyl)acetic acid (3) isreduced to not more than 3% by weight.

The crystals of salt of γ-(pyridyl)butyric acid (1) containing the saltof bis(pyridylethyl)acetic acid (3) can be purified byrecrystallization. In the recrystallization of salt ofγ-(pyridyl)butyric acid (1), water, alcohol, an aqueous solution of amineral acid or mixtures thereof can be used as a solvent.

Preparation of salt of γ-(piperidyl)butyric acid (2)

<Hydrogenation of salt of γ-(pyridyl)butyric acid (1)>

When the salt of γ-(pyridyl)butyric acid (1) is hydrogenated forconversion of the pyridine ring to a piperidine ring, the correspondingsalt of γ-(piperidyl)butyric acid (2) can be prepared. When the salt ofγ-(pyridyl)butyric acid (1) containing not more than 3% by weight ofsalt of bis(pyridylethyl)acetic acid (3) is hydrogenated, a high-puritysalt of γ-(piperidyl)butyric acid (2) can be easily formed in a shorttime.

A salt formed from a free γ-(pyridyl)butyric acid and an acid is usableas the salt of γ-(pyridyl)butyric acid (1). The salt ofγ-(piperidyl)butyric acid (2) can also be prepared by mixing an acid anda γ-(pyridyl)butyric acid, followed by hydrogenation of the mixtureinstead of hydrogenation of the salt of γ-(pyridyl)butyric acid (1).

<Catalyst>

Useful catalysts include Rh catalysts, Pd catalysts or Ru catalysts.Using a Rh catalyst or a Pd catalyst, the salt of γ-(pyridyl)butyricacid (1) can be hydrogenated under milder conditions in a shorter timefor conversion of the pyridine ring to a piperidine ring.

Examples of useful Rh catalysts, Pd catalysts or Ru catalysts includecatalysts having Rh, Pd or Ru supported on a carrier. Useful carriersare, for example, carbon, alumina and the like among which carbon ispreferred and active carbon is especially preferred. When a catalysthaving one of Rh, Pd or Ru supported on a carrier is used, the amount ofRh, Pd or Ru to be supported on the carrier is not limited, but usuallyit is 1 to 10% by weight based on the carrier.

If the amount of a Rh catalyst, a Pd catalyst or a Ru catalyst used isat least 0.05% by weight (preferably 0.05 to 0.3% by weight from theeconomical viewpoint) calculated as Rh, Pd or Ru on the basis of salt ofγ-(pyridyl)butyric acid (1), the hydrogenation of the salt ofγ-(pyridyl)butyric acid (1) easily proceeds.

If the amount of the catalyst used is less than said range, thehydrogenation entails difficulty in progress, consequently tending toinvolve a prolonged time and possibly producing the contemplated productin a lower yield for failure to complete the reaction.

<Solvent>

The salt of γ-(pyridyl)butyric acid (1) can be hydrogenated in asolvent. Useful solvents are those capable of dissolving the salt ofγ-(pyridyl)butyric acid (1) without affecting the hydrogenation thereof.For example, water is preferable for its ability to easily dissolve thesalt of γ-(pyridyl)butyric acid (1) and from the viewpoints of safetyand economy.

The amount of the solvent used should be in a range sufficient at leastto dissolve the salt of γ-(pyridyl)butyric acid (1). For example, theamount of water used is 0.5 to 10 parts by weight, preferably 1 to 3parts by weight, per part by weight of the salt of γ-(pyridyl)butyricacid (1).

If the amount of water used is below said range, the hydrogenation tendsto involve a prolonged time because of its difficulty in the progress,and the desired product may be produced in a low yield due to incompletereaction. The amount of water above said range raises no serious problembut leads to a low reactor efficiency. Accordingly the foregoing rangeis recommendable from the viewpoint of productivity.

<Reaction Conditions>

The hydrogenation can be carried out at atmospheric pressure or higherpressure, preferably a hydrogen pressure of 1 to 50 kgf/cm² (=0.1 to 5MPa). If a Rh catalyst or a Pd catalyst is used, the hydrogenation canbe efficiently conducted at a lower hydrogen pressure, e.g. 1 to 40kgf/cm², even 1 to 30 kgf/cm².

The hydrogenation can be performed at a temperature ranging from roomtemperature to 140° C., preferably 40 to 120° C. A lower reactiontemperature tends to extend the reaction time and is responsible for alow yield of desired product for the incomplete reaction. Hence it isundesirable. A higher reaction temperature presents no problem about theyield, but leads to a high reaction rate, making it difficult to controlthe temperature. Consequently said range is recommendable from theviewpoints of safety and economy.

For example, the salt of γ-(pyridyl)butyric acid (1), a catalyst and asolvent are placed into a pressure reactor equipped with a stirrer and ahydrogen inlet tube. Hydrogen is introduced through the hydrogen inlettube with heating and stirring while the mixture is maintained at theabove-mentioned hydrogen pressure and reaction temperature. Thereby thesalt of γ-(pyridyl)butyric acid (1) is hydrogenated, giving the salt ofγ-(piperidyl)butyric acid (2).

The salt of γ-(piperidyl)butyric acid (2) can also be produced whenplacing into the reactor a free γ-(pyridyl)butyric acid and an acid inplace of the salt of γ-(pyridyl)butyric acid (1). This mode of processis included in the present invention.

<Purification>

The salt of γ-(piperidyl)butyric acid (2) produced by hydrogenating thesalt of γ-(pyridyl)-butyric acid (1) can be easily isolated from thereaction mixture and purified by conventional methods such ascrystallization or recrystallization. For example, after completion ofthe hydrogenation, the reaction mixture is filtered to separate thecatalyst, and the solvent is distilled off. The resulting residue issubjected to recrystallization, whereby a high-purity salt ofγ-(piperidyl)butyric acid (2) is isolated.

EXAMPLES

The present invention is described below in greater detail withreference to the following examples to which, however, the invention isnot limited.

Example 1

A 100 ml-vol. electromagnetic agitation type autoclave (made ofHastelloy) was charged with 15.0 g (0.074 mole) of aγ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%,300 g of water and 0.75 g of 5% Rh/C [0.25% by weight in terms of Rhbased on the γ-(4-pyridyl)butyric acid hydrochloride].

The hydrogen pressure was maintained at 5 kgf/cm² (5×10⁵ Pa) whilehydrogen was introduced, and a reaction was conducted with stirring at110° C. for 1.5 hours. After completion of the reaction, the solvent wasdistilled off under reduced pressure. The residue was analyzed by highperformance liquid chromatography. The analysis showed that aγ-(4-piperidyl)butyric acid hydrochloride was produced in a yield of99%.

<Analysis conditions of high performance liquid chromatography>

Column: SHISEIDO Capcell C18 SG120 S-5 (4.6 mm (dimater)×250 mm)

Eluant: 0.02 mole/1 Aqueous solution of K₂HPO₄ (adjusted to a pH of 7.0with phosphoric acid)

Flow rate: 1.0 ml/min.

Temperature: 40° C.

Detection: UV 220 nm

Example 2

The procedure of Example 1 was repeated except the following. The samereactor as used in Example 1 was charged with 25.0 g (0.124 mole) of aγ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%,25.0 g of water and 1.25 g of 5% Rh/C [0.25% by weight in terms of Rhbased on the γ-(4-pyridyl)butyric acid hydrochloride]. The reaction wasconducted for 3 hours. A γ-(4-piperidyl)butyric acid hydrochloride wasproduced in a yield of 98%.

Example 3

The same procedure as in Example 1 was repeated except the following.The same reactor as used in Example 1 was charged with 13.5 g (0.067mole) of a γ-(4-pyridyl)butyric acid hydrochloride with a purity of atleast 99%, 27.0 g of water and 0.67 g of 5% Rh/C [0.25% by weight interms of Rh based on the γ-(4-pyridyl)butyric acid hydrochloride]. Thereaction was conducted at 60° C. for 8 hours. A γ-(4-piperidyl)butyricacid hydrochloride was produced in a yield of 97%.

Example 4

The procedure of Example 1 was repeated except the following. The samereactor as used in Example 1 was charged with 13.5 g (0.067 mole) of aγ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%,27.0 g of water and 0.67 g of 5% Pd/C [0.25% by weight in terms of Pdbased on the γ-(4-pyridyl)butyric acid hydrochloride]. The reaction wasconducted at 80° C. for 4.5 hours. A γ-(4-piperidyl)butyric acidhydrochloride was produced in a yield of 97%.

Example 5

The procedure of Example 1 was repeated except the following. The samereactor as used in Example 1 was charged with 13.5 g (0.067 mole) of aγ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%,27.0 g of water and 0.67 g of 5% Ru/C [0.25% by weight in terms of Rubased on the γ-(4-pyridyl)butyric acid hydrochloride].

The hydrogen pressure was maintained at 50 kgf/cm² (5×10⁶ Pa) whilehydrogen was introduced, and a reaction was conducted with stirring at110° C. for 5 hours. Thereafter, the solvent was distilled off underreduced pressure. The residue was analyzed by high performance liquidchromatography. The analysis showed that a γ-(4-piperidyl)butyric acidhydrochloride was produced in a yield of 98%.

Comparative Example 1

The same procedure as in Example 1 was repeated except the following.The same reactor as used in Example 1 was charged with 15.0 g (0.091mole) of γ-(4-pyridyl)butyric acid with a purity of at least 99%, 30.0 gof water and 0.75 g of 5% Rh/C [0.25% by weight in terms of Rh based onthe γ-(4-pyridyl)butyric acid]. While hydrogen was introduced, areaction was conducted with stirring at 110° C. for 5 hours.

The reaction involved a hydrogen pressure of 50 kgf/cm² (5×10⁶ Pa) andproduced γ-(4-piperidyl)butyric acid in a yield of 99%. At a hydrogenpressure of 5 kgf/cm² (5×10⁵ Pa), hydrogen was slowly absorbed, makingit difficult to hydrogenate the γ-(4-pyridyl)butyric acid.

Example 6

<Preparation of γ-(4-pyridyl)butyric acid hydrochloride>

A 1 liter-vol., 4-necked flask was charged with 34 g of an ethyl alcoholsolution containing 20 wt % sodium ethoxide (sodium ethoxide 0.1 mole)and 240 g (1.5 moles) of diethyl malonate. A 105 g (1.0 mole) quantityof 4-vinylpyridine was added dropwise over a period of 1 hour withstirring at the reflux temperature. Then, the mixture was maintained atthe reflux temperature with stirring for a further 7 hours.

After the obtained reaction mixture was cooled to room temperature, 250g of water and 111.5 g of 36 wt % hydrochloric acid (1.1 moles) wereadded. After addition of 93 g of toluene, the unreacted diethyl malonatewas collected as the organic layer. Then 101.4 g of 36 wt % hydrochloricacid (1.0 mole) was added to the aqueous layer. The mixture was kept atthe reflux temperature with stirring for 10 hours to accomplishhydrolysis and decarboxylation.

Five grams of active carbon and 8.2 g of sellaite were added to theobtained reaction mixture. After stirring for 1 hour, the mixture wasfiltered. A 167 g quantity of water was distilled off from 500 g of thefiltrate. The insolubles were removed by hot filtration. Then thefiltrate was cooled and the crystals were separated out.

The crystals were filtered and dried, giving 97.3 g of aγ-(4-pyridyl)butyric acid hydrochloride (in a yield of 48.3% based onthe 4-vinylpyridine). The obtained crystals were analyzed by highperformance liquid chromatography. The analysis showed that aγ-(4-pyridyl)butyric acid hydrochloride with a purity of 98% wasproduced and contained about 2% of bis[2-(4-pyridyl)ethyl]acetic acidhydrochloride.

<Analysis conditions of high performance liquid chromatography>

Column: SHISEIDO Capcell C18 SG120 S-5 (4.6 mm (dimater)×250 mm)

Eluant: Aqueous solution of 0.05 wt % K₂ HPO₄ (adjusted to a pH of 7.0with phosphoric acid)/methyl alcohol=50/50 (volume ratio)

Flow rate: 1.0 ml/min.

Temperature: 40° C.

Detection: UV 254 nm

<Preparation of γ-(4-piperidyl)butyric acid hydrochloride>

A 100 ml-vol., electromagnetic agitation type autoclave (made ofHastelloy) was charged with 15.0 g (0.074 mole) of the above-obtainedγ-(4-pyridyl)butyric acid hydrochloride, 30.0 g of water and 0.75 g of5% Rh/C [0.25% by weight in terms of Rh based on theγ-(4-pyridyl)butyric acid hydrochloride]. While hidrogen was introduced,the hydrogen pressure was maintained at 5 kgf/cm² (5×10⁵ Pa), and areaction was conducted with stirring at 110° C. for 1.5 hours.

After completion of the reaction, the solvent was distilled off underreduced pressure. The residue was analyzed by high performance liquidchromatography (the same analysis conditions as in Example 1). Theanalysis showed that the reaction gave a γ-(4-piperidyl)butyric acidhydrochloride in a yield of 99%.

The obtained residue was recrystallized, giving 13.0 g (yield 85%) ofcrystals of γ-(4-piperidyl)butyric acid hydrochloride with a purity ofat least 99%. The crystals contained up to 1% ofbis[2-(4-piperidyl)ethyl]acetic acid hydrochloride.

Example 7

A γ-(4-piperidyl)butyric acid hydrochloride was produced by repeatingthe same procedure as in Example 6 except that using 0.67 g of 5% Pd/C[0.25% by weight in terms of Pd based on the γ-(4-pyridyl)butyric acidhydrochloride] in place of 5% Rh/C, a reaction was conducted at 80° C.for 4.5 hours.

The reaction gave a γ-(4-piperidyl)butyric acid hydrochloride in a yieldof 97%. The obtained product was recrystallized, giving crystals ofγ-(4-piperidyl)butyric acid hydrochloride with a purity of at least 99%in a yield of 90%. The crystals contained 1% or less ofbis[2-(4-piperidyl)ethyl]acetic acid hydrochloride.

Example 8

<Preparation of γ-(4-pyridyl)butyric acid hydrochloride>

A 1 liter-vol., 4-necked flask was charged with 34 g (0.1 mole) of anethyl alcohol solution containing 20 wt % sodium ethoxide and 240 g (1.5moles) of diethyl malonate. A 105 g (1.0 mole) quantity of4-vinylpyridine was added dropwise over a period of 1 hour with stirringat the reflux temperature. Then, the mixture was maintained at thereflux temperature with stirring for a further 7 hours.

The obtained reaction mixture was cooled to room temperature, followedby addition of 250 g of water and 111.5 g (1.1 moles) of 36 wt %hydrochloric acid. After addition of 140 g of toluene, the unreacteddiethyl malonate was collected as the organic layer.

Then 220 g (1.1 moles) of 20 wt % aqueous solution of sodium hydroxidewas added to the aqueous layer. After addition of 140 g of toluene,diethyl 2-[2-(4-pyridyl)ethyl]malonate was collected as the organiclayer. After distiling off the toluene from the obtained organic layer,further distillation gave 233.5 g (0.88 mole, yield 88%) of diethyl2-[2-(4-pyridyl)ethyl]malonate.

To the obtained diethyl 2-[2-(4-pyridyl)ethyl]malonate (233.5 g) wereadded 220 g of water and 178.4 g (1.76 moles) of 36 wt % hydrochloricacid. Then, the mixture was maintained at the reflux temperature withstirring for 10 hours to accomplish hydrolysis and decarboxylation.After completion of the reaction, 4.4 g of active carbon and 7.2 g ofsellaite were added to the reaction mixture. After stirring for 1 hour,the mixture was filtered.

The obtained filtrate was analyzed by high performance liquidchromatography (the same analysis conditions as in Example 6). Theanalysis showed that a γ-(4-pyridyl)butyric acid hydrochloride wasproduced in a yield of 99%. The filtrate contained aγ-(4-pyridyl)butyric acid hydrochloride in a concentration of 35% byweight. As to the ratio of the γ-(4-pyridyl)butyric acid hydrochlorideand the bis[2-(4-pyridyl)ethyl]acetic acid hydrochloride, the former was99% and the latter 1%.

<Preparation of γ-(piperidyl)butyric acid hydrochloride>

The same reactor as used in Example 1 was charged with 42.9 g of theabove-obtained filtrate containing the γ-(4-pyridyl)butyric acidhydrochloride [15.0 g (0.074 mole) of the γ-(4-pyridyl)butyric acidhydrochloride] and 0.75 g of 5% Rh/C [0.25% by weight in terms of Rhbased on the γ-(4-pyridyl)butyric acid hydrochloride].

While hydrogen was introduced, the hydrogen pressure was maintained at 5kgf/cm² (5×10⁵ Pa), and a reaction was conducted with stirring at 50° C.for 4 hours. After completion of the reaction, the solvent was removedunder reduced pressure. The residue was analyzed by high performanceliquid chromatography (the same analysis conditions as in Example 1).The analysis showed that a γ-(4-piperidyl)butyric acid hydrochloride wasproduced in a yield of 98%. The obtained residue was recrystallized,giving crystals of γ-(4-piperidyl)butyric acid hydrochloride with apurity of at least 99% in a yield of 90%. The crystals contained 1% orless of bis[2-(4-piperidyl)ethyl]acetic acid hydrochloride.

Comparative Example 2

The procedure of Example 7 was repeated except the following. Using 0.75g of 5% Pt/C [0.25% by weight in terms of Pt based on theγ-(4-pyridyl)butyric acid hydrochloride] in place of 5% Rh/C, a reactionwas conducted for 14 hours.

After completion of the reaction, the solvent was removed and theresidue was analyzed. The analysis showed that a γ-(4-piperidyl)butyricacid hydrochloride was produced in a yield of 90% and contained 8% ofthe unreacted γ-(4-pyridyl)butyric acid hydrochloride.

Example 9

<Preparation of γ-(4-pyridyl)butyric acid hydrochloride>

A 1 liter-vol., 4-necked flask was charged with 34 g of an ethyl alcoholsolution containing 20 wt % sodium ethoxide (sodium ethoxide 0.1 mole)and 240 g (1.5 moles) of diethyl malonate. A 105 g (1.0 mole) quantityof 4-vinylpyridine was added dropwise over a period of 1 hour withstirring at the reflux temperature. The mixture was maintained at thereflux temperature with stirring for a further 7 hours.

The obtained reaction mixture was cooled to room temperature. To themixture were added 250 g of water and 111.5 g (1.1 moles) of 36 wt %hydrochloric acid. After addition of 140 g of toluene, the unreacteddiethyl malonate was collected as the organic layer.

Then 220 g (1.1 moles) of 20 wt % aqueous solution of sodium hydroxidewas added to the aqueous layer. After addition of 140 g of toluene,diethyl 2-[2-(4-pyridyl)ethyl]malonate was collected as the organiclayer.

The toluene was distilled off from the obtained organic layer. To theobtained residue were added 220 g of water and 178.4 g (1.76 moles) of36 wt % hydrochloric acid. The mixture was maintained at the refluxtemperature with stirring for 10 hours to accomplish hydrolysis anddecarboxylation. Then, 4.4 g of active carbon and 7.2 g of sellaite wereadded to the obtained reaction mixture. After stirring for 1 hour, themixture was filtered.

The obtained filtrate was analyzed by high performance liquidchromatography (the same analysis conditions as in Example 6). Theanalysis showed that a γ-(4-pyridyl)butyric acid hydrochloride wasproduced in a yield of 92%. The filtrate contained γ-(4-pyridyl)butyricacid hydrochloride in a concentration of 32.6% by weight. As to theratio of the γ-(4-pyridyl)butyric acid hydrochloride and thebis[2-(4-pyridyl)ethyl]-acetic acid hydrochloride, the former was 93%and the latter 7%.

<Preparation of γ-(piperidyl)butyric acid hydrochloride>

A γ-(piperidyl)butyric acid hydrochloride was produced in the samemanner as in Example 8 with the exception of using the filtrate obtainedabove [15.0 g (0.074 mole) of the γ-(pyridyl)butyric acid hydrochloride]as one containing the γ-(pyridyl)butyric acid hydrochloride.

The reaction required 10 hours until completion. After completion of thereaction, the solvent was removed under reduced pressure and the residuewas analyzed by liquid chromatography in the same manner as inExample 1. The analysis showed that a γ-(4-piperidyl)butyric acidhydrochloride was produced in a yield of 98%. The obtained residue wasrecrystallized, giving crystals of γ-(4-piperidyl)butyric acidhydrochloride with a purity of 93.5% in a yield of 83%. The crystalscontained 6.5% of bis[2-(4-piperidyl)ethyl]acetic acid hydrochloride.

What is claimed is:
 1. A process for preparing a salt ofγ-(piperidyl)butyric acid with an acid, the salt being represented bythe formula (2)

wherein R is a hydrogen atom or an alkyl group, and A is an acid, theprocess comprising the step of hydrogenating a salt ofγ-(pyridyl)butyric acid with an acid, the salt being represented by theformula (1)

wherein R and A are as defined above in a solvent in the presence of acatalyst, the process being characterized in that the catalyst is a Rhcatalyst, a Pd catalyst or a Ru catalyst.
 2. The process according toclaim 1, wherein the salt of γ-(pyridyl)butyric acid with an acid, thesalt being represented by the formula (1) is prepared by carrying outthe undermentioned steps (a) and (b) and contains not more than 3% byweight of a salt of bis(pyridylethyl)acetic acid with an acid, the saltbeing represented by the formula (3)

wherein R and A are as defined in claim 1: (a) reacting a vinylpyridinecompound represented by the formula (4)

wherein R is as defined in claim 1 with a diester of malonic acidrepresented by the formula (5)

wherein R¹ and R² are the same or different and each represents an alkylgroup in the presence of a base to give a diester of2-(pyridylethyl)malonic acid represented by the formula (6)

wherein R is as defined in claim 1, and R¹ and R² are as defined aboveand; (b) hydrolyzing and decarboxylating the diester of2-(pyridylethyl)malonic acid of the formula (6) prepared in the step (a)in an acidic aqueous solution to give the salt of γ-(pyridyl)butyricacid with an acid, the salt being represented by the formula (1).
 3. Theprocess according to claim 1 or 2, wherein the catalyst is Rh/C, Pd/C orRu/C.
 4. The process according to claim 1 or 2, wherein the amount ofthe catalyst used is 0.05 to 0.3% by weight in terms of a metal (Rh, Pdor Ru) based on the salt of γ-(pyridyl)butyric acid with an acid.
 5. Theprocess according to claim 1 or 2, wherein the salt ofγ-(pyridyl)butyric acid with an acid is hydrogenated at a hydrogenpressure of 1 to 50 kgf/cm².
 6. The process according to claim 1 or 2,wherein the catalyst of a Rh catalyst or a Pd catalyst.
 7. The processaccording to claim 6, wherein the catalyst is Rh/C or Pd/C.
 8. Theprocess according to claim 6, wherein the amount of the catalyst used is0.05 to 0.3% by weight in terms of a metal (Rh or Pd) based on the saltof γ-(pyridyl)butyric acid with an acid.
 9. The process according toclaim 6, wherein the salt of γ-(pyridyl)butyric acid with an acid ishydrogenated at a hydrogen pressure of 1 to 40 kgf/cm².
 10. The processaccording to claim 3, wherein the amount of the catalyst used is 0.05 to0.3% by weight in terms of a metal (Rh, Pd or Ru) based on the salt ofγ-(pyridyl)butyric acid with an acid.
 11. The process according to claim7, wherein the amount of the catalyst used is 0.05 to 0.3% by weight interms of a metal (Rh or Pd) based on the salt of γ(pyridyl)butyric acidwith an acid.